Radiation is clearly beneficial in extending the life span of patients with malignant brain tumors. Despite the initial effect of radiation therapy, the tumor generally recurs, and further treatment is most often ineffective. Our preclinical studies unexpectedly indicate that brain irradiation given before implantation can enhance subsequent tumor growth by as much as 40%. It appears that radiation alters the brain micro-environment and may stimulate tumor cell implantation and growth. The implication of these results is that previous irradiation may accelerate tumor recurrence and increase resistance to subsequent therapy. The goal of this project is to further verify this phenomenon, to elucidate the underlying mechanisms, and to evaluate its implications for therapy using animal brain tumor models. The specific aims in support of this goal are: 1) To determine if previous brain irradiation enhances the implantation rate, growth, and mass effect of subsequent neoplasms by either a) inhibiting immune activation or b) increasing the permeability of the vascular supply to the tumor and 2) To establish whether prior brain irradiation reduces the responsiveness of tumors to later doses of radiation by reducing neovascularization, increasing tumor hypoxia, and increasing tumor invasiveness. By elucidating the effects of radiation of subsequent brain tumors, this project will allow for the development of therapies that reduce the incidence of recurrent neoplasms and improve the radioresponsiveness of such tumors. [unreadable] [unreadable] [unreadable]